Add Salt To Taste For Negishi Cross-Couplings

Chemists find that salt additives affect aryl- and alkylzinc reagents differently

Steve Ritter

Since its discovery in 1977, the Nobel Prize-winning Negishi cross-coupling reaction has been widely used for stitching together two organic groups to make complex molecules, ranging from antibiotics to electroactive compounds in light-emitting diodes. Even so, chemists this year found new insight into the role salt additives play in driving specific types of Negishi couplings. This fundamental observation means chemists no longer need to rely on one set of standard reaction conditions for all couplings. Instead, they can pick and choose conditions to optimize couplings, in some cases eliminating salt additives when they aren’t needed to create greener reactions. In Negishi cross-couplings, a zinc reagent is typically prepared from an organometallic precursor and a zinc halide. The zinc reagent then transfers its organic group to a palladium catalyst, a process known as transmetalation. The palladium complex then mediates C–C coupling of the organic group with a second organic group contributed by an organohalide. Lucas C. McCann and Michael G. Organ of York University, in Toronto, concluded after a decade of investigations that aryl- and alkylzinc halide reagents require a metal halide salt additive such as LiCl for cross-coupling to occur, whereas diarylzinc reagents work without the salt additive and dialkylzinc reagents don’t work at all (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201400459). The key, Organ explains, is matching the selected zinc starting reagent with the appropriate solvent polarity, which can be augmented by adding the salt if required, to form the active zinc transmetalating species.

A salt additive such as LiCl is necessary in some cases for Negishi cross-couplings to succeed.

A salt additive such as LiCl is necessary in some cases for Negishi cross-couplings to succeed.

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